Dataset Information

Isolation and Characterization of an HLA-DPB1*04: 01-restricted MAGE-A3 T-Cell Receptor for Cancer Immunotherapy.

ABSTRACT: Long-term tumor regressions have been observed in patients following the adoptive transfer of autologous tumor-infiltrating lymphocytes or genetically modified T cells expressing MHC class I-restricted T-cell receptors (TCRs), but clinical trials have not evaluated responses to genetically modified T cells expressing antitumor MHC class II-restricted TCRs. As studies carried out in a murine tumor model system have demonstrated that the adoptive transfer of CD4 T cells could lead to the regression of established tumors, we plan to test the hypothesis that CD4 T cells can also induce tumor regressions in cancer patients. In this study, 2 MAGE-A3-specific TCRs were isolated from a regulatory T-cell clone (6F9) and an effector clone (R12C9), generated from the peripheral blood of 2 melanoma patients after MAGE-A3 vaccination. The results indicated that T cells transduced with 6F9 TCR mediated stronger effector functions than R12C9 TCR. The 6F9 TCR specifically recognized MAGE-A3 and the closely related MAGE-A6 gene product, but not other members of the MAGE-A family in the context of HLA-DPB1*04:01. To test the feasibility of a potential clinical trial using this TCR, a clinical-scale procedure was developed to obtain a large number of purified CD4 T cells transduced with 6F9 TCR. Because HLA-DPB1*04:01 is present in ?60% of the Caucasian population and MAGE-A3 is frequently expressed in a variety of cancer types, this TCR immunotherapy could potentially be applicable for a significant portion of cancer patients.

SUBMITTER: Yao X

PROVIDER: S-EPMC4947411 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Publications

Isolation and Characterization of an HLA-DPB1*04: 01-restricted MAGE-A3 T-Cell Receptor for Cancer Immunotherapy.

Yao Xin X Lu Yong-Chen YC Parker Linda L LL Li Yong F YF El-Gamil Mona M Black Mary A MA Xu Hui H Feldman Steven A SA van der Bruggen Pierre P Rosenberg Steven A SA Robbins Paul F PF

Journal of immunotherapy (Hagerstown, Md. : 1997) 20160601 5

Long-term tumor regressions have been observed in patients following the adoptive transfer of autologous tumor-infiltrating lymphocytes or genetically modified T cells expressing MHC class I-restricted T-cell receptors (TCRs), but clinical trials have not evaluated responses to genetically modified T cells expressing antitumor MHC class II-restricted TCRs. As studies carried out in a murine tumor model system have demonstrated that the adoptive transfer of CD4 T cells could lead to the regressio ...[more]

PMID: 27163739

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Project description:OBJECTIVES:Tissue transglutaminase autoantibodies (tTGAs) represent the first evidence of celiac disease (CD) development. Associations of HLA-DR3-DQA1*05:01-DQB1*02:01 (i.e., DR3-DQ2) and, to a lesser extent, DR4-DQA1*03:01-DQB1*03:02 (i.e., DR4-DQ8) with the risk of CD differ by country, consistent with additional genetic heterogeneity that further refines risk. Therefore, we examined human leukocyte antigen (HLA) factors other than DR3-DQ2 for their contribution to developing tTGAs. METHODS:The Environmental Determinants of Diabetes in the Young (TEDDY) study enrolled 8,676 infants at an increased HLA-DR-DQ risk for type 1 diabetes and CD into a 15-year prospective surveillance follow-up. Of those followed up, 21% (n=1,813) carried DR3-DQ2/DR3-DQ2, 39% (n=3,359) carried DR3-DQ2/DR4-DQ8, 20% (n=1701) carried DR4-DQ8/DR4-DQ8, and 17% (n=1,493) carried DR4-DQ8/DQ4. Within TEDDY, a nested case-control design of 248 children with CD autoimmunity (CDA) and 248 matched control children were genotyped for HLA-B, -DRB3, -DRB4, -DPA1, and -DPB1 genes, and the entire cohort was genotyped for single-nucleotide polymorphisms (SNPs) using the Illumina ImmunoChip. CDA was defined as a positive tTGA test at two consecutive clinic visits, whereas matching in those with no evidence of tTGAs was based on the presence of HLA-DQ2, country, and sex. RESULTS:After adjustment for DR3-DQ2 and restriction to allele frequency (AF) ?5%, HLA-DPB1*04:01 was inversely associated with CDA by conditional logistic regression (AF=44%, odds ratio=0.71, 95% confidence interval (CI)=0.53-0.96, P=0.025). This association of time to CDA and HLA-DPB1*04:01 was replicated with statistical significance in the remainder of the cohort using imputation for specific HLA alleles based on SNP genotyping (hazard ratio=0.84, 95% CI=0.73-0.96, P=0.013). CONCLUSIONS:HLA-DPB1*04:01 may reduce the risk of tTGAs, an early marker of CD, among DR3-DQ2 children, confirming that additional variants in the HLA region influence the risk for CDA.

Dataset Information

Isolation and Characterization of an HLA-DPB1*04: 01-restricted MAGE-A3 T-Cell Receptor for Cancer Immunotherapy.

Publications

Isolation and Characterization of an HLA-DPB1*04: 01-restricted MAGE-A3 T-Cell Receptor for Cancer Immunotherapy.

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